Malaria is the number one infectious disease in the world today. Notwithstanding that it was believed that malaria was close to becoming eradicated in the 1960's with the use of quinine, chloroquine and DDT, it was not. Rather malaria is an ever growing problem throughout the world. Approximately 200 million people in endemic areas are infected annually. Worldwide, over two million people die each year from malaria. This shocking reality is due in part to the emergence of drug resistant strains of Plasmodium falciparum, the most lethal malarial parasite known to date. More specifically, a high percentage of malaria today is caused by chloroquine-resistant Plasmodium falciparum.
Artemisinin (Qinghaosu), first isolated by the Chinese from the leaves of Artemisia annua in 1972, is known to be a fast acting, safe and effective drug against chloroquine-resistant and sensitive strains of Plasmodium falciparum, as well as against cerebral malaria. No side effects, common to many synthetic antimalarials, have been reported by the Chinese during the past six years of clinical use of artemisinin. Unfortunately, one of the disadvantages o artemisinin is that the compound is only sparingly soluble in either water or oils and thus not readily absorbable by the gastrointestinal tract. Another disadvantage of the drug resides is the fact that large doses (3.times.400 mg/day per patient) of the drug are required for therapetic efficacy. A more ideal drug with enhanced antimalarial activity and improved physical and bioavailability properties is an urgent need to treat chloroquine-resistant malaria.
In U.S. Pat. No. 4,920,147 to McChesney and Jung, there is described a novel method of preparing deoxoartemisinin comprising essentially a one-step process of directly reducing artemisinin, derived from the leaves of Artemisia annua, with a mild reducing agent followed by refluxing the mixture to yield the deoxoartemisinin.
The structural complexity of artemisinin, particularly the presence of a peroxide bridge which must be preserved for drug efficacy and chemically sensitive lactone ring, has rendered the preparation of derivatives of artemisinin without a carbonyl function extremely difficult. This difficulty is one of the reasons that the method described in the aforementioned patent represents such an advance in the art; however, the yields of deoxoartemisinin produced by the method of the patent is limited by the availability of artemisinin. Moreover, there has not been any practical method of preparing derivatives of (+)-deoxoartemisinin and compounds which are analogues of deoxoartemisinin useful as antimalarial agents. The new compounds are producible in extremely large quantities from the same quantity of-leaves of Artemisia annua required to prepare the small amounts of deoxoartemisinin prepared using the method of the prior art. In accordance with the method of the invention, (+)-deoxoartemisinin may be prepared simply and practically in quantities substantially six times greater than the known method using as a starting material artemisinic acid derived from the leaves of Artemisia annua.